How to Build a Living Thing VMASAcHu T EIE OF TECHN ^ ,. Y by EN 0 9 2009 MacGregor Campbell LIBRARIES B.S. Physics Duke University, 2001 Submitted to the Program in Writing and Humanistic Studies in Partial Fulfillment of the Requirements for the Degree of Master of Science in Science Writing at the ARCHIVES Massachusetts Institute of Technology September 2009 @ MacGregor Campbell. All rights reserved. The author hereby grants to MIT permission to reproduce and to distribute publicly paper and electronic copies of this thesis document in whole or in part in any medium now known or hereafter created. Signature of Author ................ ........................... ................. Graduate Program in Science Writing May 20, 2009 Certified by .......... ........ ................ ............. ............ Thomas Levenson Professor of Science Writing _4,irector, Graduate Program in Science Writing Accepted by....... ....... ........... ............ Thomas Levenson sor of Science Writing Director, Graduate Program in Science Writing How to Build a Living Thing by MacGregor Campbell Submitted to the Program in Writing and Humanistic Studies on May 20, 2009 in partial fulfillment of the requirements for the degree of Master of Science in Science Writing ABSTRACT A number of research groups worldwide are working on various aspects of the problem of building life from scratch. Jack W. Szostak's lab in Cambridge, Massachussets is one of the centers of the action. Open a recent news article on some discovery related to synthetic life or life's origins on Earth, and he's likely to be quoted. Szostak fills his lab with ambitious, bright, young people, a few of whom have gone on to found their own labs. His work provides a lens through which to view the contemporary state of progress toward the ancient and ambitious goal to take what was not alive before and make it live. Starting from an initial plan to make a self-assembling, self-replicating membrane containing a self-replicating genetic molecule, the lab has had some striking successes and, off course, some setbacks. Recent breakthroughs suggest that the realization of a wholly human-designed and created life form looms in the foreseeable future. Thesis Advisor: Tom Levenson Title: Director, Graduate Program in Science Writing Acknowledgement Thank you to the Szostak Lab at Massachussets General Hospital for their patient explanations and for giving me open access to their people and process. Thank you also to my advisor, Tom Levenson. How to Build a Living Thing A translucent hairy pickle, visible only under the microscope, Tetrahymena thermophilia spends its days floating in temperate bodies of freshwater, motoring around with its thousands of tiny hairs, snacking on passing bits of debris. Most people wouldn't distinguish it from pond scum because it is, in fact, pond scum. To scientists, however, this little protozoan has yielded critical secrets about how life works. In the early 1980s it told a young researcher at the University of Colorado named Thomas Cech what might turn out to be the biggest one of all. It used to be assumed that cells observed a strict division between Labor and Management. DNA knew what to do; complex molecular machines called ribosomes knew how to do it. In 1980, everybody knew that RNA was just a messenger, a molecular errand-boy relaying instructions from DNA in a cell's nucleus to the ribosomes in charge of making the larger molecules required to keep a cell alive. The intricate work of the cell was handled by protein enzymes, twisty, folded molecules whose physical shape allows them to facilitate otherwise unlikely chemical reactions. But with T. thermophilia'shelp, Cech discovered that such strict division of labor did not always hold in nature. He found that some strands of T. thermophilia's RNA could snip off pieces of themselves without the help of proteins. This humble reaction turned molecular biology on its head: now enzymes weren't limited to being made of proteins, they could be made of RNA. Cech and Sidney Altman--who found a similar phenomenon at Yale--won the 1989 Nobel Prize for Chemistry, for this discovery. With the ability to both store information and catalyze reactions, the possibility arose that RNA might be a biological entrepreneur, simultaneously directing and carrying out the functions of a simple cell. Life based solely on RNA became a feasible idea, though it had never been observed before in nature. Many began to believe that RNA-based life might have preceded the current world of DNA, RNA, and proteins. Nobel Laureate Walter Gilbert coined the term "RNA world" in 1986 to describe such a primordial Earth. Origins researchers imagined seas, or at least pools, of RNA molecules having different properties, undergoing a form of molecular evolution. Some molecules might be active enough to make copies of themselves. These would have an advantage, population-wise, over molecules that couldn't. Mutations that led to better replication would drive evolution and set in motion the chain of events that billions of years later would lead to dogs and human beings. The problem is that all of this would have happened somewhere around 3.5 to four billion years ago. Scientists believe that fossil evidence of the event would have long been destroyed. This leaves two options for anyone interested in figuring out how life might have started on Earth. The first is to look at the geological record and speculate about what chemicals might have been present, what the early oceans were like, what the atmosphere was like, and imagine possible chemical routes to life. The second is to put on the lab coat and safety goggles and actually try to make it happen right now. Cech's discovery of ribozymes hinted that this second approach might be feasible. A little less than twenty years after the breakthrough, a group of scientists who had been working on origins of life problems, Jack Szostak of the Howard Hughes Medical Institute, David Bartel of MIT's Whitehead Laboratory, and Pier Luigi Luisi of the Institut fOr Polymere in Switzerland set out to see just how powerful a ribozyme might be. They called their shot in a January 2001 issue of the journal Nature, laying out a roadmap to build a simple primitive cell-a protocell. The paper was called "Synthesizing Life", and in it they claimed it would be possible for humans to do what had never been done before: build a living thing, from scratch, in the laboratory. A number of research groups worldwide are working on various aspects of the problem of building life from scratch. Szostak's lab in Cambridge, Massachussets is one of the centers of the action. Open a recent news article on some discovery related to synthetic life or life's origins on Earth, and he's likely to be quoted. He fills his lab with ambitious, bright young people, a few of whom have gone on to found their own labs. His work provides a lens through which to view the contemporary state of progress toward the ancient and ambitious goal to take what was not alive before and make it live. Sitting in his wood-paneled office, Jack Szostak's calm open-ness conceals a core of ambition and brilliance. With glasses and a roundish face-Carl Zimmer once wrote that he looks like an "affable owl"-he's quick to smile and is commonly referred to by students and colleagues as "great." He's a scientific jack-of-all-trades, "If you want to do a project like this, you have to be willing to go from molecular biology to biophysics to organic chemistry, just do whatever's necessary," he said. Szostak is fascinated by the question of how life began on Earth, but in his current research, he does not intend to retrace the steps that life actually took. More than that: he is doubtful that anyone can prove the exact sequence of pre- historical events. Instead he would be very happy at his stage to build any sort of chemical system that might be considered alive. His roadmap paper in Nature laid out the essential task plainly: "The first challenge on the path to a synthetic life form is to imagine a collection of molecules that is simple enough to form by self-assembly, yet sufficiently complex to take on the essential properties of a living organism." Simple and complex: a yeast cell, one of the simplest single-celled organisms, has about 3,000 genes, each one encoding the instructions needed to build a protein. The proteins in turn interact with each other and smaller molecules, sugars, for example, to carry out chemical reactions, like respiration or protein synthesis, required to keep the yeast cell alive. With millions of moving parts, each carrying out a delicate yet necessary task, a modern living cell is masterpiece of complexity, well beyond what a scientist could hope to design from scratch. Presumably, however, life wasn't always this complicated. Assuming that a living system had to at some point be simple enough to form on its own from pieces that were not alive before, Szostak, Bartel, and Luisi broke the problem down further, "We can consider life as a property that emerges from the union of two fundamentally different kinds of replicating systems: the informational genome and the three-dimensional structure in which it resides." Reducing the larger problem of life to the two comparatively simple problems of a self-replicating genome-presumably a bit of RNA to drive cellular reactions and pass information to future generations-and a self-replicating 3D structure-to keep the system together-provided a glimpse of the way forward. Inspired by Cech's work, a functioning information molecule would serve as a proof of concept for the RNA world.